Pathogenesis of Hepatic Encephalopathy in

Acute Liver Failure

Javier Vaquero, M.D.,1,2 Chuhan Chung, M.D.,2 Michael E. Cahill, B.A.,2 and
Andres T. Blei, M.D.2

ABSTRACT

Hepatic encephalopathy (HE) in acute liver injury signifies a serious prognosis.

Brain edema and intracranial hypertension are major causes of death in this syndrome.
Comparison of HE in acute liver failure (ALF) with that of cirrhosis allows recognition
of important differences and similarities. A key role for ammonia in the pathogenesis of

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both HE and brain edema is now firmly supported by clinical and experimental data. Ad-
ditional factors, such as infection, products of the necrotic liver, and synergistic toxins,
may contribute to an altered mental state. A low plasma osmolarity, high temperature,
and both high and low arterial pressure may affect brain water content. A combined de-
rangement of cellular osmolarity coupled with cerebral hyperemia can explain the devel-
opment of brain edema in ALF. Increasingly, study of the mechanisms responsible for
brain swelling provides critical information for understanding the pathogenesis of HE.

KEYWORDS: Hepatic encephalopathy, brain edema, acute liver failure, ammonia,

cerebral blood flow

Objectives: Upon completion of this article, the reader should be able to (1) understand the key role played by ammonia in the
pathogenesis of hepatic encephalopathy and brain edema in acute liver failure and (2) recognize the influence of other important ad-
ditional factors in the development of these complications.
Accreditation: Tufts University School of Medicine (TUSM) is accredited by the Accreditation Council for Continuing Medical Educa-
tion to provide continuing medical education for physicians. TUSM takes responsibility for the content, quality, and scientific in-
tegrity of this CME activity.
Credit: TUSM designates this educational activity for a maximum of 1 Category 1 credit toward the AMA Physicians Recognition
Award. Each physician should claim only those credits that he/she actually spent in the educational activity.

T he development of HE in patients with ALF
signals a critical phase of the illness (also defined as ful-
minant hepatic failure1) and is associated with a reduced
survival. In epidemiological studies performed in the pre-
transplant era, spontaneous recovery of liver function was
70% in stages I and II encephalopathy and was reduced
to < 20% in stages III and IV encephalopathy.2 Death in
hepatic coma is common in patients with cirrhosis and
advanced liver failure, but a unique feature of ALF is
death from cerebral edema and intracranial hypertension.

Fulminant Hepatic Failure; Editor in Chief, Paul D. Berk, M.D.; Guest Editor, Roger Williams, C.B.E., M.D., FRCP, FRCS, FRCPE, FRACP,
F.Med.Sc., FRCPI (Hon), FACP (Hon). Seminars in Liver Disease, volume 23, number 3, 2003. Address for correspondence and reprint requests:
Dr. Andres T. Blei, Searle 10–573, 303 East Chicago Ave., Chicago, IL, 60611. E-mail: a-blei@northwestern.edu. 1Post-doctoral Research
Fellow, 2Section of Hepatology, Department of Medicine, Lakeside Veterans Administration Medical Center and Northwestern University
Feinberg School of Medicine, Chicago, Illinois. Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662. 0272–8087,p;2003,23,03,259,270,ftx,en;sld00229x.

259
260 SEMINARS IN LIVER DISEASE/VOLUME 23, NUMBER 3 2003
A CLINICAL OVERVIEW: COMPARISON OF
HE IN ALF AND CIRRHOSIS
Encephalopathy in ALF shares features and exhibits
differences with the encephalopathy of cirrhosis. Five
aspects deserve specific consideration.
Grading of HE
The West Haven criteria, designed for clinical studies in
cirrhosis,3 have also been used in patients with ALF.
However, the precise characteristics of each stage often
overlap, and differences between stages I and II or be-
tween II and III can be blurred. Certain clinical features
of ALF are not well-represented in this classification,
especially severe agitation, which can be an initial neu-
rological symptom in ALF and pose serious problems in
management (including the need to sedate the patient
with loss of neurological end points for follow-up). An
excitatory behavioral phase is consistent with robust ex-
perimental findings of an increased extracellular brain
glutamate in this condition.4
Once stage IV encephalopathy is reached, the
Glasgow coma scale, initially developed for patients with
neurotrauma,5 provides a numerical continuous score
from 3 (worst) to 15 (best). Although it has not been
formally evaluated in metabolic encephalopathies, it is
better suited for examining patients in stages III and IV
encephalopathy than the West Haven criteria, as was
recently shown.6
Precipitating Factors
The pathogenic role of precipitating factors, well-recog-
nized in the encephalopathy of cirrhosis, is often over-
looked in ALF. Patients with acute liver failure may
develop encephalopathy from the use of sedatives, as dis-
turbances of sleep or agitation may be an early prodrome
and are often medicated prior to arrival at a specialized
center. Gastrointestinal hemorrhage, uremia, and elec-
trolyte disturbances need to be ruled out. Infection, how-
ever, is the key precipitant to consider; the role of infec-
tion is discussed in the next section.
Seizures
Seizures have traditionally been viewed as a rare event
in hepatic encephalopathy. A retrospective review of elec-
troencephalogram tracings in 94 patients with cirrhosis
described epileptiform abnormalities in 14% of subjects
with deep encephalopathy who did not receive a liver
transplant.7
Seizure activity has been reported in previous clin-
ical series of ALF8 and is a well-recognized complica-
tion of acute hyperammonemia in urea-cycle disorders.9
In a recent controlled trial, subclinical seizure activity
was detected in 10 of 22 patients enrolled as controls in
a trial of prophylactic phenytoin in ALF.10 Measure-
ments of low oxygen saturation in the jugular vein led to
the conclusion that poor cerebral perfusion and tissue
anoxia were potential determinants of seizure develop-
ment. At autopsy, patients in the nontreated group had
greater evidence of cerebral edema. The high frequency
of subclinical seizures reported in this series awaits con-
firmation from other centers.
Brain Edema
Death from intracranial hypertension has now been re-
ported in patients with cirrhosis and deep hepatic en-
cephalopathy in the setting of acute-on-chronic liver
failure.11,12 The magnetization transfer ratio, an indirect
reflection of brain water content on spectroscopy, was
clearly abnormal in patients with cirrhosis,13 suggesting
low-grade brain edema. The paradigm has shifted, with
an increasing realization that a disturbance in brain water
regulation is central to the process responsible for he-
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patic encephalopathy.14,15 Nonetheless, a neurological
death is a rare event in patients with cirrhosis.
Cerebral Perfusion
In cirrhosis, a reduction in cerebral blood flow has been
described in patients with overt16 and minimal17 encepha-
lopathy. A hyperdynamic circulatory state is a character-
istic finding in liver failure, and the response of the
cerebral circulation needs to be considered in this con-
text. Recently, Guevara and colleagues18 postulated a di-
rect relation between the reduction in cerebral and renal
blood flow in patients with cirrhosis and ascites. The
decrease in perfusion of both territories was viewed as a
response to systemic arterial vasodilatation, a sequence
well-accepted for the renal vasoconstriction of cirrho-
sis.19 The absence of signs of encephalopathy in these
patients adds further credence to the view that the cere-
bral circulation also reacts to the generalized hemody-
namic disturbance of liver failure.20 In ALF, an initial
reduction of cerebral blood flow (CBF) may reflect sim-
ilar mechanisms.21 However, a rise in CBF is promi-
nently seen in patients with overt brain edema.22
PATHOGENESIS OF HE IN ALF—
SYSTEMIC FACTORS
Conceptually, hepatic encephalopathy arises from expo-
sure of the brain to circulating neurotoxins. In an early
stage of research in this area, the absence of a critical
trophic factor for brain function was postulated.23 Re-
cently, this idea has been revived in experiments per-
formed in isolated liver-brain preparations.24 However,
multiple elements point at the role of circulating toxins,
most conclusively the development of HE in the pres-
ence of a normal liver.25
 HEPATIC ENCEPHALOPATHY/VAQUERO ET AL 261

Ammonia splanchnic release of ammonia, derived from the break-

A pathogenic role for ammonia has been the focus of
experimental and clinical studies. Death from cerebral
edema and intracranial hypertension is well-recognized
in children with urea cycle enzyme deficiencies and severe
hyperammonemia.9 In human ALF, arterial ammonia
levels > 200 µg/dL were associated with cerebral hernia-
tion within 24 hours of reaching stage III–IV encepha-
lopathy.26 These data have been subsequently confirmed27
and point at levels of < 150 µg/dL as a cutoff below
which the risk of neurological death may be substantially
decreased.
Arterial sampling is important, because AV dif-
ferences of ammonia can be considerable in ALF. In a
recent human study, arterial concentration was 160 ± 53
versus 110 ± 35 µg/dL in the femoral vein, a significant
difference.28 Under normal circumstances (Fig. 1), the
down of glutamine in the intestine and the increased ac-
tivity of colonic bacteria, results in 10-fold higher levels
of ammonia in the portal vein. An efficient hepatic up-
take mechanism, related to both urea (high capacity, low
affinity) and glutamine (low capacity, high affinity) syn-
thesis, results in tight control of ammonia levels reach-
ing the periphery, with a hepatic extraction rate of 0.8 to
0.9.29 In ALF, hepatic vein measurements showed higher
levels of ammonia (242 ± 118) than those seen in arterial
blood (182 ± 80 µg/dL, n = 22).28 In the setting of an
acutely failing liver, ammonia levels in the hepatic vein
are similar to those seen in the portal vein.
Muscle uptake of this increased ammonia load
results in the formation of glutamine. Whereas release
and recirculation of glutamine will result in the regener-
ation of ammonia, splanchnic generation of ammonia

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Figure 1 Interorgan trafficking of ammonia and glutamine. In normal conditions, gut release of ammonia results in high portal vein
ammonia levels. Ammonia is efficiently removed by the liver via the urea cycle and glutamine synthesis, resulting in lower levels of
ammonia in hepatic venous blood compared with arterial levels. Under normal conditions, arterial ammonia values are tightly con-
trolled. In ALF, the liver extracts portal venous ammonia poorly. The subsequent increase of arterial ammonia levels leads to in-
creased disposition of ammonia in other tissues. Both the brain and muscle lack a complete urea cycle and rely on the formation of
glutamine. Thus, the brain and muscle become ammonia-uptake and glutamine-releasing organs. Because the regeneration of am-
monia from glutamine that will occur in the intestines and kidney appears to have a saturation point, the capacity of the muscle to
detoxify ammonia represents a potential therapeutic target. Finally, the capacity of the kidney to excrete ammonia in ALF is under
investigation.
262 SEMINARS IN LIVER DISEASE/VOLUME 23, NUMBER 3 2003
appears saturable.28 Thus, the capacity of muscle to detox-
ify ammonia may be of importance. Ornithine-aspartate
stimulates muscle glutamine synthetase in experimental
ALF and prevents the development of brain edema.30
The role of amino acids in ammonia disposal in ALF
deserves further attention.
A net uptake of ammonia also occurs in the
brain,28 where it amidates both alpha-ketoglutarate and
glutamate.31 Glutamine is formed and cycles from as-
trocytes to presynaptic neurons, where glutamate is
formed. After release into the synaptic cleft, reuptake of
glutamate occurs in astrocytes. A profound alteration of
this cycle has been demonstrated in experimental stud-
ies31 and underlies the development of brain edema.
Recent studies have raised the possibility that the
kidney may be an important route for ammonia elimi-
nation in cirrhosis.32 Such findings await additional con-
firmation. In any case, the extent of renal ammonia
elimination in ALF may be affected by the development
of renal failure, a common finding in this syndrome.
Infection
A classic precipitant factor of the encephalopathy in
chronic liver disease is the development of infection.
Recent clinical observations indicate a strong associa-
tion between parameters of infection and the course of
encephalopathy in ALF33 (see Bernal34 in this issue). A
recent report from the U.S. Acute Liver Failure Study
group supports and extends these observations.35 Only
patients with early encephalopathy were analyzed. In a
prospective evaluation of acetaminophen-induced ALF
(n = 96), a positive diagnosis of infection preceded or
coincided with the progression of stage I–II to deeper
stages of encephalopathy in 79% of individuals. In sub-
jects without demonstrable infection, a group that in-
cluded both acetaminophen and nonacetaminophen
etiologies (n = 168), a greater number of components of
the systemic inflammatory response syndrome (SIRS)
Table 1 Definition of SIRS
The systemic inflammatory response to a variety of severe
clinical insults.103
The response is manifested by two or more of the following
conditions:
Temperature > 38 °C or < 36 °C
Heart rate > 90 beats/min
Respiratory rate > 20 breaths/min or PaCO2 < 32 torr
(< 4.3 kPa)
WBC > 12,000 cells/mm3, < 4000 cellls/mm3, or > 10%
immature (band) forms
From: Muckart DJ, Bhagwanjee S. American College of Chest
Physicians/Society of Critical Care Medicine Consensus Confer-
ence: definitions of the systemic inflammatory response syndrome
and allied disorders in relation to critically injured patients. Crit Care
Med 1997;25:1789–1795
was associated with a stepwise progression of encepha-
lopathy from 25% (0 components), 34.7% (1 compo-
nent), and 50% (2 to 3 components).35 An explanation of
the components of SIRS can be found in Table 1.
How infection triggers encephalopathy in liver
failure is poorly understood. The encephalopathy of sep-
sis is not similar to that of ALF.36 Binding of cytokines
to receptors in cerebral endothelial cells with subsequent
signal transduction into the brain is a likely scenario.37
Interactions of this process with other toxins, such as
ammonia, have not been examined and may yield im-
portant clues to the pathogenesis of HE.
The Necrotic Liver
Scattered reports indicate improvement of the clinical con-
dition in ALF after total hepatectomy.38 In two well-stud-
ied cases, intracranial pressure was reduced and liver trans-
plantation successfully performed when a donor organ
became available.39,40 A reduction in liver-derived cy-
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tokines was suggested as a reason for this beneficial ef-
fect.40 However, critical examination of this experience
notes the development of mild to moderate hypothermia
after removal of the liver. Reductions of temperature to 32
to 35°C have been associated with reductions in brain
edema and intracranial pressure in both experimental
models41 and human ALF.42 In a controlled trial of hypo-
thermia in patients with head trauma, reduced levels of in-
terleukin (IL)-1 accompanied body temperatures of
34°C.43 At this time, the role of the necrotic liver in the de-
velopment or progression of encephalopathy is uncertain.
Synergism
In the mid-1970s, Zieve and Nicoloff44 coined the con-
cept of “synergistic toxins,” in which a wide array of gut-
derived substances potentiated ammonia’s deleterious ef-
fects on the brain. These studies focused on mortality
associated with ammonia administration to rats, noting
a reduction of the LD50 of ammonia with the addition
of short-chain fatty acids, mercaptans, and phenols. Oc-
tanoic acid had previously received attention as a puta-
tive cause of brain edema in Reye’s syndrome.45 Its role
in ALF is uncertain.
The impact of compounds that cross the blood-
brain barrier and activate gamma-aminobutyric acid
(GABA)–ergic pathways has undergone a vast change
since originally proposed more than 20 years ago. Al-
though the existence of endogenous benzodiazepine lig-
ands in the brain of patients with ALF has been reported
previously,46 current evidence supports a potentiating
effect of ammonia on GABA-induced neurotransmis-
sion.47 These aspects are discussed in greater detail else-
where in this issue.48
Tryptophan is an amino acid whose levels are in-
creased in the plasma of patients with ALF.49 Its entry

into the brain is favored by activation of the neutral
amino acid carrier at the level of the blood-brain barrier
in exchange for glutamine, the brain levels of which are
increased as a result of ammonia detoxification in astro-
cytes. Tryptophan is a precursor of serotonin, but the role
of serotoninergic abnormalities in the encephalopathy
of ALF is uncertain. A report of increased brain quino-
linic acid, a peripheral derivative of tryptophan, in human
brain does not suggest a major role for this pathway in
the encephalopathy of ALF.50
BRAIN EDEMA: PART OF THE
SPECTRUM OF HE
For many years, the presence of brain edema was viewed
as a unique complication of ALF, a distinct entity from
the classic picture of HE. Our views on this separation
have undergone major changes in recent years. The re-
sults of in vitro studies, animal experimentation, and
human data point at a common disturbance of water ac-
cumulation, present in the entire spectrum of clinical
manifestations (Fig. 2). According to this view, the clin-
ical expression of brain edema, a rise in intracranial
pressure, is prominent in ALF but can also be detected
in subjects with cirrhosis and deep hepatic coma.11,12 New
technical developments have allowed the estimation of
an increased water content in the brain of patients with
cirrhosis,13 supporting the notion of low-grade brain
edema.14
In 1999, we proposed a mechanism responsible
for the development of brain edema based on a combi-
nation of experimental and clinical observations.51 An
initial osmotic disturbance of the brain, when combined
with an increase in cerebral blood flow, results in this
unique complication of liver failure. Many of our views
of the pathogenesis of brain edema and intracranial hy-
pertension have originated from work in the rat after
Figure 2 The spectrum of hepatic encephalopathy. An increasing amount of data points to a common disturbance of brain water
accumulation underlying the entire spectrum of neurological manifestations of both acute and chronic liver disease. The intensity
and acuteness of the insult, together with the influence of other concurrent systemic factors, will determine which part of this spec-
trum will be clinically apparent.
HEPATIC ENCEPHALOPATHY/VAQUERO ET AL 263
portacaval anastomosis receiving an ammonia infusion.
Although this model is not one of ALF, the reliable de-
velopment of brain edema within a few hours of infu-
sion allows the study of factors responsible for swelling
in the absence of confounding variables seen in the set-
ting of ALF. Such variables may also be critically im-
portant and will be reviewed after we espouse our basic
concepts.
An Osmotic Disturbance
SELECTIVE CELLULAR SWELLING
Brain edema represents a net increase in total brain water
content. Multiple studies point at cortical astrocytes as
the cellular element initially swollen in ALF. An ana-
tomic breakdown of the blood-brain barrier is not a fea-
ture of ALF, as noted in experimental models52,53 and
after examination of cerebral capillaries in human brain.54
Neuroanatomic studies are difficult to perform in autopsy
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material,54 so animal models have been very useful for
supporting a primary event in astrocytes.52,53 Further-
more, isolated astrocytes can be induced to swell when
exposed to some of the circulating toxins of liver fail-
ure.55 The demonstration of astrocyte swelling in ani-
mals with portacaval anastomosis alone56 supports a
spectrum of changes, in which glial swelling can occur
without brain edema. The term low-grade brain edema
has been coined for this earlier disturbance of water ho-
meostasis.14
CHANGES IN ORGANIC OSMOLYTES
Direct measurements in experimental animals57 and nu-
clear magnetic resonance (NMR) spectroscopic findings
in humans58 have repeatedly shown a marked increase in
brain glutamine, the product of ammonia detoxification
in astrocytes. Inhibition of glutamine synthetase prevents
264 SEMINARS IN LIVER DISEASE/VOLUME 23, NUMBER 3 2003
ammonia-induced swelling of isolated astrocytes59 as
well as brain edema in vivo.60,61 The increase in brain
glutamine can be fourfold to sixfold, although the lim-
ited capacity of astrocytic glutamine synthetase results
in a steady high level of glutamine throughout the course
of the neurological disturbance.
Cells exhibit short- and long-term adaptive mech-
anisms to adjust for changes in osmolarity.62 A high ex-
tracellular brain potassium has been shown to occur
acutely in an experimental model of acute hyperam-
monemia,63 consistent with the effects of regulatory
volume decrease in isolated cells.62 Potassium levels are
increased in the jugular vein of patients with ALF,64 sug-
gesting an increased exit from brain tissue. In the case of
chronic adaptation, reduction of the levels of myoinosi-
tol, a key intracellular organic osmolyte, is accomplished
slowly over several days.62 Such osmotic adaptation may
be a factor that explains the lower frequency of brain
edema in subacute or subfulminant hepatic failure.65 Con-
sistent with these temporal changes in osmotic adapta-
tion is the finding of an elevated glutamine and a low
brain myoinositol in patients with cirrhosis, as seen with
brain NMR spectroscopy.58
An Increase in Cerebral Blood Flow
In 1986, Ede and Williams66 observed an increase of
CBF in a subset of patients with ALF and deep HE.
They proposed this increased CBF reflected the systemic
vasodilatation seen in ALF. Subsequent clinical studies
showed a more complex picture. In a series of 30 pa-
tients with ALF, Wendon et al67 noted a wide range of
values of CBF, with most having reduced CBF. In an
American series, 24% of patients had an elevated CBF,
which was associated with brain edema and a higher
mortality.22
CEREBRAL ANOXIA IN ALF?
The cerebral metabolic rate for oxygen (CMRO2) can
be estimated in humans by the product of CBF and the
arteriovenous oxygen difference. A small cerebral ar-
teriovenous oxygen difference (arterial-jugular vein con-
tent) was seen in many of the patients with low or nor-
mal CBF,67 which is suggestive of tissue anoxia. In ALF,
values of CMRO2 are low, in some cases less than those
thought necessary to maintain cerebral viability.68 How-
ever, these patients can achieve a full neurological recov-
ery after transplantation.22,67
Alternatively, the finding of a low CMRO2 in
patients with normal CBF may be indicative of relative
hyperemia, with a dissociation of CBF and the brain’s
metabolic needs.69 In order to study the response of
CMRO2 to alterations in CBF, Larsen and colleagues70
measured blood flow and oxygen extraction after infu-
sion of noradrenaline. Their findings indicate a preser-
vation of cerebral oxidative metabolism, arguing against
the concept of tissue anoxia.
FAILURE OF CEREBROVASCULAR AUTOREGULATION
Under normal conditions, cerebral autoregulation main-
tains a stable CBF in the face of fluctuations in systemic
pressure. The limits of autoregulation, between 60 and
160 mmHg, can be shifted in chronic disease states such
as arterial hypertension. In resistance vessels, a myogenic
component of autoregulation is normally based on the
rapid response of vascular smooth muscle to changes in
transmural pressure. In ALF, Larsen assessed the cere-
brovascular autoregulation after a noradrenaline chal-
lenge. When mean arterial pressure rose by 30 mmHg,
transcranial Doppler measurements in the middle cere-
bral artery showed an increase of velocity of 41%.71 This
loss of autoregulation was restored within 1 day after liver
transplantation or within 4 days in subjects with spon-
taneous recovery. Of note, the therapeutic use of hypo-
thermia also restored cerebrovascular autoregulation in
a series of 14 patients with ALF.72
RESPONSE TO CHANGES IN PCO2
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Under normal conditions, the cerebral circulation re-
sponds exquisitely to changes in hypercapnia and hypo-
capnia with concomitant vasodilatation and vasoconstric-
tion, respectively. CBF changes linearly from 2 to 4%
for every millimeter of mercury change in pCO2, also
termed the CO2 reactivity coefficient. Hypoxia must be
profound, with a pO2 less than 60 mmHg triggering
cerebral vasodilatation.73
In patients with ALF, evidence supports the exis-
tence of a dilated cerebral vasculature. Hyperventilation
leading to hypocapnia results in an appropriate reduc-
tion in CBF.74 Furthermore, it can restore cerebrovas-
cular autoregulation.75 Hypercapnia, however, does not
result in further increases in CBF,74 an indicator of a
markedly reduced CO2-reactivity coefficient. In an al-
ready dilated cerebral vasculature, further vasodilatory
stimuli are unlikely to result in additional effects.
MECHANISMS
In our experimental model, a predictable and selective
rise in CBF occurs prior to the development of brain
edema and intracranial hypertension in the setting of
stable systemic hemodynamics.61,76 Two important ob-
servations have been made in this model that shed light
on the pathogenesis of this complex phenomenon.
1. Brain edema can be prevented with measures that im-
pede the rise in CBF. Both indomethacin77 and mild
hypothermia41 have been shown to reduce CBF and
prevent the development of brain swelling and in-
tracranial pressure (ICP) elevation. The case of in-
domethacin is especially significant as the drug has
limited entry into the brain. Whereas hypothermia
exhibits multiple effects on brain metabolism, vaso-
constriction induced by indomethacin can be effective
in human disease.78 An increase in blood flow may
underlie the movement of water into brain following

the principles of Starling’s law, as recently postulated
by Larsen and Wendon.70
2. The signal that triggers the increase in CBF occurs after the
generation of glutamine in astrocytes. Inhibition of gluta-
mine synthesis with methionine-sulfoximine amelio-
rates the rise in CBF seen in our model.76 This com-
pound also restores the cerebrovascular response to CO2
in normal rats,60 suggesting that an impaired cerebral
autoregulation develops once glutamine is generated.
The link between the synthesis of glutamine and
the subsequent onset of cerebral hyperemia is a critical
question in this model and has not been elucidated. The
finding of a high nitric oxide (NO) efflux from the sagit-
tal sinus76 raised a possible role for NO generated from
an increased activity of neuronal NO synthase.80 How-
ever, selective and nonselective inhibitors of this enzyme
failed to prevent the rise in CBF.81 The high CBF val-
ues seen in human ALF in deep coma highlight the im-
portance of the search for a brain-derived signal that re-
sults in cerebral hyperemia. An increase in blood flow is
associated with an increase in ammonia uptake,82 a fac-
tor that has recently been shown to increase the likeli-
hood of cerebral herniation in patients with ALF.83
OXIDATIVE AND NITROSATIVE STRESS: PATHOGENIC
MECHANISMS IN BRAIN EDEMA AND HE?
Several recent observations support the presence of ox-
idative and nitrosative stress in the brain of models of
HE. The formation of free radicals can be indirectly sur-
mised from a series of clinical and experimental observa-
tions. In humans, lipofuscin pigment, reflecting the per-
oxidation of lipids, can be detected in Alzheimer type II
astrocytes.84 We have shown an increase in gene expres-
sion of brain heme oxygenase-1 and the reduction of
Cu/Zn superoxide dismutase in rats after portacaval anas-
tomosis, findings that support the presence of oxidative
stress.85 Activities of neuronal NO synthase are increased
in this model,86 and we have reported an increase in brain
NO efflux, another free radical, in rats after portacaval
anastomosis receiving an ammonia infusion.76
The strongest evidence for this concept arises from
cellular studies. The formation of free radicals can be
detected in astrocytes exposed to ammonia.87 Astrocytes
exposed to ammonia also develop the mitochondrial per-
meability transition (MPT).88 This effect, in which the
opening of a large nonselective pore in mitochondria re-
sults in morphological and functional abnormalities, leads
to defective oxidative phosphorylation and to the gener-
ation of even more free radicals. Cultured neurons did
not develop the MPT when exposed to ammonia.88 In
support of a pathogenic role of glutamine, inhibition of
glutamine synthetase prevented the development of the
MPT in isolated astrocytes exposed to ammonia.88
Free radicals can nitrosylate proteins, and nitroty-
rosine, a stable product of this reaction, can be demon-
strated in isolated astrocytes exposed to ammonia.89 This
HEPATIC ENCEPHALOPATHY/VAQUERO ET AL 265
finding can also be seen in vivo.89 We have recently com-
pleted preliminary studies in rats after portacaval anasto-
mosis receiving an ammonia infusion. Clear evidence of
nitrotyrosine accumulation in astrocytes was noted (Fig.
3). The functional implications of these changes and
their relation to the pathogenesis of HE is an evolving
concept but one likely to be important in the manifesta-
tions of HE in both ALF and cirrhosis.
CLINICAL PATHOPHYSIOLOGY
In the previous section, we analyzed paradigms that
have evolved from experimental models. Clinical ob-
servations support the role of such pathophysiological
mechanisms.
Plasma Osmolarity
Earlier series of patients with ALF had noted hypona-
tremia in patients with encephalopathy.90 In the experi-
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mental animal, hyponatremia (mean serum sodium of
117) aggravates ammonia-induced brain edema.91 The
osmotic disturbance in the brain of patients with ALF
is anisosmotic, reflecting the generation of osmoles within
the brain,62 and will be potentiated by a decrease in
plasma osmolarity. Patients with cirrhosis who developed
intracranial hypertension after placement of a trans-
jugular intrahepatic portal-systemic stent-shunt (TIPS)
were all hyponatremic.11 Further support of this concept
can be seen with the deterioration of mental state asso-
ciated with rapid fluid shifts in hemodialysis.92
Temperature
Fever aggravates the clinical picture in ALF.93 Fever
(> 38ºC) is a component of SIRS, as described earlier,
and in experimental animals, an increase in cerebral
blood flow and metabolic rate accompanies the hyper-
thermic state.94 Preliminary evidence supports an asso-
ciation between temperatures above 38ºC and the de-
velopment of intracranial hypertension in patients with
ALF.95 Whereas fever can accompany systemic infec-
tion, septic encephalopathy is associated with an intact
cerebrovascular CO2 reactivity and pressure autoregula-
tion,36 a conspicuous difference with the changes seen
in human ALF.
Arterial Pressure
As a consequence of the loss of cerebrovascular autoreg-
ulation, patients with ALF are susceptible to the effects
of both a reduction and an increase in arterial pressure.
Cerebral ischemia can ensue as a result of the former.
Cerebral hyperemia, the result of the latter, can aggra-
vate the development of brain edema. Maintenance of
an adequate level of blood pressure is critical to prevent
either possibility.
266 SEMINARS IN LIVER DISEASE/VOLUME 23, NUMBER 3 2003

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Figure 3 Staining for nitrotyrosine in the cerebral cortex of a portacaval-shunted rat receiving an ammonia infusion. The upper
right-hand picture shows glial fibrillary acidic protein (GFAP) positive astrocytes in the cerebral cortex. The upper left-hand picture
shows nitrotyrosine staining in astrocytes; the lower right-hand picture reveals the overlap of GFAP and nitrotyrosine staining in cor-
tical astrocytes. Methods: Ammonia (55 µmol/kg/min) was infused through the femoral vein for 3 hours. At the end of the infusion,
the brain was fixed by the perfusion-fixation method. After blocking with 1% bovine serum albumin (BSA) and 5% goat serum, cere-
bral cortex sections were incubated overnight in rabbit antinitrotyrosine antibody (Upstate Group [Charlottesville, VA], 1:75) at 4°C
followed by incubation in Alexa Fluor 488 antirabbit secondary antibody (Molecular Probes [Eugene, OR], 1:400) for 1 hour at 25°C.
Following nitrotyrosine staining, astrocytes labeling was revealed with an overnight incubation in mouse anti-GFAP antibody (Chemi-
con International [Temecula, CA], 1:1000) at 4°C followed by incubation in Alexa Fluor 568 anti–mouse secondary antibody (Molecu-
lar Probes, 1:400) for 1 hour at 25°C. The fluorescent-stained slides were scanned using a LSM 510 confocal microscope.

Glucose ventricular size is a common finding.101 Swelling of the

A recently proposed candidate for a synergistic role in the
development of intracranial hypertension in ALF is hy-
perglycemia. In a preliminary report, values > 12 mmol/L
(> 200 µg/dL) were associated with higher values of
ICP.96 In other neurological conditions, hyperglycemia
is known to aggravate the effects of brain trauma97 and
ischemia98 in relation to the increased generation of brain
lactate as a result of anaerobic glycolysis. Lactate levels
are increased in the brain of experimental models99 and
human100 ALF, although the mechanism responsible for
the rise may be different.100
gray matter, where astrocytes constitute 30% of the cellular
elements, has been recently demonstrated using NMR
techniques.102 Although cerebral blood volume is difficult
to measure, the presence of cerebral vasodilatation and hy-
peremia suggests an increase in this compartment. With
the enlargement of the cellular compartment and in the
setting of a limited compliance imposed by the rigid skull,
small increases in blood volume will cause an inordinate
rise in ICP. The article by Jalan et al103 in this issue pro-
vides further insight into the monitoring and management
of intracranial hypertension.

The Rise in Intracranial Pressure CONCLUSION

Water in the brain exists in three forms: intracellular water, Our article has highlighted the close relationship be-
blood, and cerebrospinal fluid. The latter is decreased in tween the process that results in brain edema and the
ALF, as seen in imaging of the brain in which shrinking of pathogenesis of hepatic encephalopathy. ALF is a good

example of how factors traditionally thought to account
for brain edema are also implicated in the pathogenesis
of hepatic encephalopathy. Elucidation of the mecha-
nisms responsible for brain water accumulation is likely
to provide new insights into rational therapeutic ap-
proaches to hepatic encephalopathy.
ACKNOWLEDGMENTS
Supported by a Merit Review from the VA Research
Administration and the Stephen B. Tips Memorial Fund
at Northwestern Memorial Hospital. Dr. Vaquero is sup-
ported by Fondo de Investigacion Sanitaria (BEFI/
FIS), Madrid, Spain.
ABBREVIATIONS
ALF acute liver failure
CBF cerebral blood flow
CMRO2 cerebral metabolic rate of oxygen
HE hepatic encephalopathy
ICP intracranial pressure
NMR nuclear magnetic resonance
NO nitric oxide
SIRS systemic inflammatory response syndrome
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